The insulin receptor of the plasma membrane consists of a heterodimer comprised of an alpha and beta subunit. The mature receptor is synthesized by way of a 190 K proreceptor. However, the mechanism of conversion of the proreceptor to the mature subunit is unknown. Inasmuch as the proteosome is an important mechanism of both processing and degrading intracellular proteins, it is of interest to determine whether the proteosome may be involved in the processing of the proreceptor to the mature receptor. Further, inasmuch as it is known that insulin bound to the mature plasma membrane receptor is largely degraded by both neutral and lysosomal proteases, degradation of the internalized receptor is not well understood. In part the receptor is recycled back to the plasma membrane, but portions of the receptor are also degraded intracellularly. Thus, it is of interest to know what role, if any, the proteosome may play in this process. Recently, several specific inhibitors of proteosome degradation have been developed, and it is, therefore, possible to ask whether or not these inhibitors have an effect on the degradation of the mature endocytosed insulin receptor as well as on the processing of the proreceptor. Thus, two types of protocols are under study. The first utilizes the binding of insulin to cultured cells, followed by endocytosis and measurements of hormone and receptor degradation both in the absence and the presence of specific proteosome inhibitors. The second type of protocol involves biosynthetic labeling of the proreceptor and its fate in the absence and presence of other specific inhibitors of proteosome degradation. The initial results do not demonstrate an effect of the inhibitor on the mature membrane localized or endocytosed receptor. In contrast, the inhibitor decreases the conversion rate of the newly synthesized receptor. This effect on processing of the receptor is similar to the CFTR, which also presents the paradox of how an extracellular step is affected by the cytoplasmic proteosome. - insulin receptor, proteosome, endocytosis, proteolysis, post-translational processing